Once thought to be merely an inert storage depot for excess energy, adipose tissue is now recognized as an active endocrine and paracrine organ secreting multiple mediators, known as adipokines, that participate in diverse metabolic processes. The polypeptide adipokine adiponectin is the most abundant known factor secreted by adipocytes and accounts for approximately 0.01% of plasma protein. Whereas levels of other adipokines increase with fat mass, adiponectin levels vary inversely with fat mass/obesity. Decreased adiponectin levels are also observed in type 2 diabetes and cardiovascular disease. The strong correlation between low levels of circulating adiponectin, or hypoadiponectinemia, and risk factors for these major diseases may derive partly from adiponectin's anti-inflammatory properties, which contrast with the proinflammatory character of other adipokines (Szmitko et al., 2007, Am J Physiol Heart Circ Physiol 292:H1655-H1663). Thus, adiponectin appears to function as the protective adipokine, counterbalancing the potentially detrimental actions of these other adipokines.
Considerable evidence has emerged linking hypoadiponectinemia with cardiovascular disease (Szmitko et al., supra). Adiponectin levels in patients with coronary heart disease or cerebrovascular disease are lower than in healthy controls (Hotta et al., 2000, Arterioscler Thromb Vasc Biol 20:1595-1599; Kumada et al., 2003, Arterioscler Thromb Vasc Biol 23:85-89; Pischon et al., 2004, JAMA 291:1730-1737) and vary inversely with the severity of disease. Hypoadiponectinemia is associated with increased risk of cardiovascular disease even in nonobese individuals (Im et al., 2006, Metabolism 55:1546-1550). Significantly, adiponectin inhibits development of atherosclerosis in animal models (Okamoto et al., 2002, Circulation 106:2767-2770), providing evidence for a causal relationship between low adiponectin levels and cardiovascular disease. Therefore, there is a need for ActRIIB-derived agents and other inhibitors of ActRIIB signaling that can be used to treat or prevent hypoadiponectinemia.